Amidopyrimidone derivatives

Abstract

The present invention provides compounds of formula I or II: wherein X 1 , X 3 , R 1 , R 2 , R 3 , R 4 and R 5 are as described herein, as well as pharmaceutically acceptable salts thereof. Further the present invention is concerned with the manufacture of the compounds of formula I, pharmaceutical compositions comprising them and their use as medicaments.

1 . A compound formula I or II: 
       
         
           
           
               
               
           
         
         wherein 
         X 1  is either N or CH; 
         X 3  is either N or CR 3    
         the dotted line represents a single bond when R 5  is oxo or a double bond when R 5  is —NH 2 , 
         R 1  is (C 1 -C 6 )alkyl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R 1a , (C 1 -C 6 )alkoxy optionally substituted with one or more, particularly one to three, more particularly one or two substituents R 1b , halo(C 1 -C 6 )alkyl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R 1a , halo(C 1 -C 6 )alkoxy optionally substituted with one or more, particularly one to three, more particularly one or two substituents R 1b , (C 3 -C 8 )cycloalkyl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R 1c , heteroaryl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R 1d , heterocycloalkyl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R 1e  or phenyl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R 1f ; 
         R 1a  and R 1b  are each independently selected from (C 3 -C 6 )cycloalkyl, hydroxyl, heteroaryl, heterocycloalkyl and phenyl, wherein heteroaryl, heterocycloalkyl or phenyl are optionally substituted with one or more, particularly one to three, more particularly one or two substituents R 1g ; 
         R 1c , R 1d , R 1e  and R 1f  are each independently selected from halogen, oxo, cyano, hydroxyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl-(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl, heteroaryl, heterocycloalkyl and phenyl; 
         R 1g  are each independently selected from halogen, cyano, hydroxyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl-(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy, hydroxy(C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl; 
         R 2  is hydrogen, halogen, amino, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R 2a , (C 3 -C 6 )cycloalkyl-(C 1 -C 6 )alkyl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R 2b , (C 3 -C 6 )cycloalkyl-(C 1 -C 6 )alkoxy optionally substituted with one or more, particularly one to three, more particularly one or two substituents R 2c , heterocycloalkyl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R 2d NR 2f R 2g  or phenyl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R 2e ; 
         R 2a , R 2b , R 2c , R 2d  and R 2e  are each independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl and halo(C 1 -C 6 )alkoxy; 
         R 2f  and R 2g  are each independently selected from hydrogen or (C 1 -C 6 )alkyl; 
         R 3  is hydrogen, halogen, cyano, amino, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R 3a , (C 3 -C 6 )cycloalkyl-(C 1 -C 6 )alkyl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R 3b , (C 3 -C 6 )cycloalkyl-(C 1 -C 6 )alkoxy optionally substituted with one or more, particularly one to three, more particularly one or two substituents R 3c , heterocycloalkyl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R 3d  or phenyl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R 3e ; 
         R 3a , R 3b , R 3c , R 3d  and R 3e  are each independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl and halo(C 1 -C 6 )alkoxy; 
         R 4  is hydrogen, cyano, hydroxy, halogen, amino, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl-(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R 4a , (C 3 -C 6 )cycloalkyl-(C 1 -C 6 )alkyl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R 4b , (C 3 -C 6 )cycloalkyl-(C 1 -C 6 )alkoxy optionally substituted with one or more, particularly one to three, more particularly one or two substituents R 4c , heterocycloalkyl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R 4d , —CO 2 R 4a  or —CONR 4b R 4c ; 
         R 4a , R 4b , R 4c  and R 4d , R 4e  are each independently selected from hydrogen and (C 1 -C 6 )alkyl; and 
         R 5  is —NH 2  or oxo; 
         or pharmaceutically acceptable salts thereof. 
       
     
     
         2 . (canceled) 
     
     
         3 . The compound of  claim 1 , wherein the compound is of formula I′: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , wherein the compound is of formula I″: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 1 , wherein X 3  is CR 3 . 
     
     
         6 . The compound of  claim 1 , wherein X 1  is N. 
     
     
         7 . The compound of  claim 1 , wherein R 1  is (C 1 -C 6 )alkyl optionally substituted with one R 1a , (C 3 -C 6 )cycloalkyl optionally substituted with one R″ °, heteroaryl optionally substituted with one or two R 1d , heterocycloalkyl optionally substituted with one R 1e  or phenyl optionally substituted with one or two R 1f . 
     
     
         8 . The compound of  claim 1 , wherein R 1  is (C 1 -C 3 )alkyl optionally substituted with one R 1a , (C 3 -C 6 )cycloalkyl optionally substituted with one R 1c , pyrazolyl optionally substituted with one R 1d , indazolyl optionally substituted with one R 1d , indolyl optionally substituted with one R 1d , benzo[d]oxazolyl optionally substituted with one R 1d , benzo[d]thiazolyl optionally substituted with one R 1d , benzo[d]imidazolyl optionally substituted with one R 1d , dioxepanyl optionally substituted with one R 1d , oxazolyl optionally substituted with one R 1d , thiazolyl optionally substituted with one R 1d , pyridinyl optionally substituted with one or two R 1d , pyrimidinyl optionally substituted with one R 1d , dihydropyrrolo[1,2-c]imidazolyl optionally substituted with one R 1e , oxepanyl optionally substituted with one R 1e , dihydro-indolyl optionally substituted with one R 1e , 1,4-dioxepanyl optionally substituted with one R 1e , tetrahydrofuranyl optionally substituted with one R 1e , tetrahydropyranyl optionally substituted with one R 1e , piperidinyl optionally substituted with one R 1e , oxaspiro[2.5]octanyl optionally substituted with one R 1e , dihydrobenzofuranyl optionally substituted with one R 1e  or phenyl optionally substituted with one or two R 1f . 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . The compound of  claim 1 , wherein R 1  is tetrahydropyranyl optionally substituted with one (C 1 -C 3 )alkyl in alpha. 
     
     
         15 . The compound of  claim 1 , wherein R 1  is heteroaryl substituted with one or two R 1d  wherein at least of one R 1d  is substituted in ortho, heterocycloalkyl substituted with one R 1e  substituted in alpha or phenyl substituted with one or two R 1f  wherein at least of one R 1f  is substituted in ortho. 
     
     
         16 . The compound of  claim 1 , wherein R 1  is pyridinyl substituted with one or two R 1d  wherein at least of one R 1d  is substituted in ortho, tetrahydrofuranyl substituted with one R 1e  substituted in alpha, tetrahydropyranyl substituted with one R 1e  substituted in alpha, oxaspiro[2.5]octanyl or 2,3-dihydrobenzofuranyl substituted with one R 1e . 
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . The compound of  claim 1 , wherein R 1a  and R 1b  are each independently selected from heteroaryl, heterocycloalkyl and phenyl. 
     
     
         20 . The compound of  claim 1 , wherein R 1a  is selected from tetrahydrofuranyl, pyridinyl, oxetanyl or oxazolyl. 
     
     
         21 . The compound of  claim 1 , wherein R 1c , R 1d , R 1e  and R 1f  are each independently selected from halogen, oxo, cyano, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl and halo(C 1 -C 6 )alkoxy. 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . (canceled) 
     
     
         25 . The compound of  claim 1 , wherein R 1  is 2,3-dihydrobenzofuranyl, 2-hydroxycyclopentyl, 3-hydroxycyclopentyl, 1-(tetrahydrofuran-2-yl)ethyl, 1-tetrahydrofuran-3-yl-ethyl, 1-pyridin-2-yl-ethyl, oxepan-3-yl, 1,4-dioxepan-6-yl, dihydro-1H-indol-4-yl, 1-(oxetan-3-yl)ethyl, 1-(oxazol-5-yl)ethyl, indazol-4-yl, oxaspiro[2.5]octanyl, 4-methyloxazol-5-yl, 2-methoxy-phenyl, 3-methyl-phenyl, 2-methyl-phenyl, 3-fluoro-2-methoxyphenyl, 2-methylbenzonitrile, 2-methoxybenzonitrile, 2-ethoxybenzonitrile, 2-chlorophenyl, 3-chlorophenyl, 4-fluoro-2-methylphenyl, 3-fluoro-2-methylphenyl, 3-fluorophenyl, 2-fluorophenyl, 2,6-difluorophenyl, 2,3-dimethylphenyl, phenyl, 2,3-difluorophenyl, 2-fluoro-3-methylphenyl, 3-methoxyphenyl, 3,5-difluorophenyl, 3,4-difluorophenyl, 2-trifluoromethyl-phenyl, 3-(fluoromethyl)-2-methylphenyl, 3-ethylphenyl, 3-chloro-2-fluorophenyl, 2-chloro-5-fluorophenyl, 2-chloro-4-fluorophenyl, 2,3-dichlorophenyl, benzo[d]oxazol-4-yl, benzo[d]imidazolyl, benzo[d]thiazol-7-yl, 2-oxopiperidin-4-yl, 2-methylpyrazol-3-yl, 1-ethyl-1H-pyrazol-5-yl, 2-methylpyridin-3-yl, picolinonitrile, 2-methoxypyridin-3-yl, 2-(trifluoromethyl)pyridin-3-yl, 4-methylpyridin-3-yl, 4-fluoro-2-methoxypyridin-3-yl, indolyl, 2-chloropyridin-3-yl, 6-methoxypyridin-2-yl, 4-methylpyrimidin-5-yl, trifluoromethoxypyridin-2-yl, dihydrobenzofuranyl, tetrahydrofuranyl, 4-methyltetrahydrofuran-3-yl, methyl-tetrahydro-2H-pyran-3-yl, 6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl or 4-methylthiazol-5-yl, 
     
     
         26 . (canceled) 
     
     
         27 . (canceled) 
     
     
         28 . (canceled) 
     
     
         29 . The compound of  claim 1 , wherein R 2  is hydrogen, halogen, amino, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R 2a , (C 3 -C 6 )cycloalkyl-(C 1 -C 6 )alkyl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R 2b , (C 3 -C 6 )cycloalkyl-(C 1 -C 6 )alkoxy optionally substituted with one or more, particularly one to three, more particularly one or two substituents R 2e  heterocycloalkyl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R 2d  or phenyl optionally substituted with one or more, particularly one to three, more particularly one or two substituents R 2e ; and
 R 2a , R 2b , R 2c , R 2d  and R 2e  are each independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl and halo(C 1 -C 6 )alkoxy.   
     
     
         30 . (canceled) 
     
     
         31 . (canceled) 
     
     
         32 . (canceled) 
     
     
         33 . (canceled) 
     
     
         34 . The compound of  claim 1 , wherein R 2  is trifluoromethyl, difluoromethoxy, trifluoromethoxy or cyclopropyl. 
     
     
         35 . The compound of  claim 1 , wherein R 2a , R 2b , R 2c , R 2d  and R 2e  are each independently selected from halogen and (C 1 -C 6 )alkyl. 
     
     
         36 . (canceled) 
     
     
         37 . (canceled) 
     
     
         38 . The compound of  claim 1 , wherein R 2f  and R 2g  are each independently selected from hydrogen or (C 1 -C 3 )alkyl, particularly wherein one of R 2f  and R 2g  is hydrogen while the other is (C 1 -C 3 )alkyl. 
     
     
         39 . (canceled) 
     
     
         40 . The compound of  claim 1 , wherein R 3  is hydrogen, chloro, fluoro or cyano. 
     
     
         41 . (canceled) 
     
     
         42 . The compound of  claim 1 , wherein R 3a , R 3b , R 3c , R 3d  and R 3e  are each independently selected from halogen and (C 1 -C 3 )alkyl. 
     
     
         43 . The compound of  claim 1 , wherein R 4  is hydrogen, cyano, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or —CONR 4b R 4c . 
     
     
         44 . (canceled) 
     
     
         45 . (canceled) 
     
     
         46 . The compound of  claim 1 , wherein R 4b  or R 4c  are hydrogen. 
     
     
         47 . The compound of  claim 1 , wherein R 5  is —NH 2 . 
     
     
         48 . The compound of  claim 1 , selected from the group consisting of:
 4-amino-7-cyclopropyl-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-cyclopropyl-1-(2-methoxyphenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-(tert-butyl)-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-1-(2-methoxyphenyl)-7-phenylpyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-(3,3-difluoroazetidin-1-yl)-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-cyclopropyl-1-(tetrahydrofuran-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-cyclopropyl-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-cyclopropyl-1-(2-oxopiperidin-4-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-cyclopropyl-1-((cis)-2-methyltetrahydrofuran-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one;   4-amino-7-cyclopropyl-1-(o-tolyl)pyrido[4,3-d]pyrimidin-2 (1H)-one;   4-amino-7-cyclopropyl-1-(2-methylpyridin-3-yl)quinazolin-2-one;   4-amino-7-cyclopropyl-1-(2-methylphenyl)quinazolin-2-one;   7-cyclopropyl-1-(2-methylphenyl)quinazoline-2,4-dione;   4-amino-7-cyclopropyl-1-(o-tolyl)pyrimido[4,5-d]pyrimidin-2 (1H)-one;   7-cyclopropyl-1-(2-methylpyridin-3-yl)quinazoline-2,4-dione;   4-amino-7-cyclopropyl-1-(2-methoxypyridin-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-cyclopropyl-6-fluoro-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   7-cyclopropyl-1-(2-methylphenyl)pyrido[2,3-d]pyrimidine-2,4-dione;   3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1 (2H)-yl)picolinonitrile;   4-amino-7-cyclopropyl-1-(oxan-3-yl)pyrido[2,3-d]pyrimidin-2-one;   4-amino-7-cyclopropyl-1-[1-(oxolan-3-yl)ethyl]pyrido[2,3-d]pyrimidin-2-one;   4-amino-7-cyclopropyl-1-(3-fluoro-2-methoxyphenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1 (2H)-yl)-2-methylbenzonitrile;   4-amino-1-(2-methylpyridin-3-yl)-7-propan-2-ylpyrido[2,3-d]pyrimidin-2-one;   4-amino-7-cyclopropyl-1-(2,3-dihydrobenzofuran-4-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-6-chloro-7-cyclopropyl-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1 (2H)-yl)-2-methoxybenzonitrile;   3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1 (2H)-yl)-2-ethoxybenzonitrile;   4-amino-7-cyclopropyl-1-(1-(tetrahydrofuran-2-yl)ethyl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-1-(2-methylpyridin-3-yl)-7-(oxetan-3-yl)quinazolin-2 (1H)-one;   7-cyclopropyl-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4-dione;   4-amino-7-((1RS,2RS)-2-methylcyclopropyl)-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-cyclopentyl-1-(2-methyl-3-pyridyl)pyrido[2,3-d]pyrimidin-2-one;   4-amino-7-cyclopropyl-1-((1SR,2RS)-2-hydroxycyclopentyl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-2-cyclopentyl-7-(o-tolyl)pyrazolo[3,4-d]pyrimidin-6-one; formic acid;   4-amino-7-cyclopentyl-1-(4-methylpyrimidin-5-yl)pyrido[2,3-d]pyrimidin-2-one;   4-amino-7-cyclopropyl-1-(3-fluoro-2-methylphenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-cyclopropyl-1-[(3R)-oxan-3-yl]pyrido[2,3-d]pyrimidin-2-one;   4-amino-7-cyclopropyl-1-[(3S)-oxan-3-yl]pyrido[2,3-d]pyrimidin-2-one;   4-amino-7-cyclopropyl-1-(4-methyltetrahydrofuran-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-cyclopropyl-2-oxo-1-(0-tolyl)-1,2-dihydropyrido[2,3-d]pyrimidine-5-carboxamide;   4-amino-1-(2-methoxy-3-pyridyl)-7-tetrahydropyran-2-yl-pyrido[2,3-d]pyrimidin-2-one;   4-amino-7-[(1S,4R)-3-azabicyclo[2.2.1]heptan-3-yl]-1-(2-methylpyrazol-3-yl)pyrido[2,3-d]pyrimidin-2-one; formic acid;   4-amino-1-(2-methylpyridin-3-yl)-7-(trifluoromethyl)quinazolin-2-one;   4-amino-7-cyclopropyl-1-[rac-(2R,3 S)-2-methyloxolan-3-yl]pyrido[2,3-d]pyrimidin-2-one;   4-amino-7-cyclobutyl-1-(2-methyl-3-pyridyl)pyrido[2,3-d]pyrimidin-2-one; formic acid;   4-amino-7-cyclopropyloxy-1-(2-methylpyridin-3-yl)quinazolin-2-one;   4-amino-1-(2-methylpyridin-3-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-(7-azabicyclo[2.2.1]heptan-7-yl)-1-(4-methylthiazol-5-yl)pyrido[2,3-d]pyrimidin-2-one; formic acid;   4-amino-7-cyclopropyl-1-(3-hydroxycyclopentyl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-(difluoromethoxy)-1-(2-methylpyridin-3-yl)quinazolin-2 (1H)-one;   4-amino-7-(difluoromethyl)-1-(2-methylpyridin-3-yl)quinazolin-2 (1H)-one;   4-amino-7-[(1R,2S)-2-fluorocyclopropyl]-1-(2-methyl-3-pyridyl)pyrido[2,3-d]pyrimidin-2-one;   4-amino-7-cyclopropyl-1-(2-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile;   3-(4-amino-7-isopropyl-2-oxopyrido[2,3-d]pyrimidin-1 (2H)-yl)-2-methoxybenzonitrile;   4-amino-7-cyclopropyl-2-oxo-1-(0-tolyl)-1,2-dihydropyrido[2,3-d]pyrimidine-5-carbonitrile;   4-amino-7-methoxy-1-(2-methylpyridin-3-yl)quinazolin-2 (1H)-one;   4-amino-1-(2-methylpyridin-3-yl)-7-(trifluoromethoxy)quinazolin-2 (1H)-one;   4-amino-7-(4,5-dihydrofuran-3-yl)-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-1-(2-methylpyridin-3-yl)-7-(tetrahydrofuran-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-cyclopropyl-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2-one;   4-amino-7-cyclopropyl-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2-one;   4-amino-7-cyclopropyl-1-(4-methylthiazol-5-yl)pyrido[2,3-d]pyrimidin-2-one;   4-amino-7-cyclopropyl-1-(4-methylpyrimidin-5-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one,   4-amino-7-cyclopropyl-1-(2-(trifluoromethyl)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one;   4-amino-7-cyclopropyl-1-(2-methylpyrazol-3-yl)pyrido[2,3-d]pyrimidin-2-one;   4-amino-7-cyclopropyl-1-(2,3-dihydrobenzofuran-4-yl)quinazolin-2 (1H)-one;   (R)-4-amino-1-(tetrahydro-2H-pyran-3-yl)-7-(trifluoromethyl)quinazolin-2 (1H)-one;   4-amino-7-cyclopropyl-1-(4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-ethyl-1-(2-methylpyridin-3-yl)quinazolin-2 (1H)-one;   4-amino-7-[(1S,2R)-2-fluorocyclopropyl]-1-[(3R)-tetrahydropyran-3-yl]pyrido[2,3-d]pyrimidin-2-one;   4-amino-7-cyclopropyl-1-(4-methyloxazol-5-yl)pyrido[2,3-d]pyrimidin-2-one;   3-(4-amino-6-chloro-7-isopropyl-2-oxopyrido[2,3-d]pyrimidin-1 (2H)-yl)-2-methoxybenzonitrile;   4-amino-7-cyclopropyl-1-((R)-1-((S)-tetrahydrofuran-3-yl)ethyl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-cyclopropyl-1-((R)-1-((R)-tetrahydrofuran-3-yl)ethyl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-(2-fluoropropan-2-yl)-1-(2-methylpyridin-3-yl)quinazolin-2-one;   4-amino-5-methoxy-1-(2-methylpyridin-3-yl)-7-(trifluoromethyl)quinazolin-2 (1H)-one;   4-amino-7-cyclopropyl-1-(4-fluoro-2-methoxypyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one;   4-amino-5-fluoro-1-(2-methylpyridin-3-yl)-7-(trifluoromethyl)quinazolin-2 (1H)-one;   4-amino-7-cyclopropyl-1-(1-ethyl-1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-chloro-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-cyclopropyl-1-(2,3-dihydrobenzofuran-7-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   1-amino-4-(2-methoxyphenyl)-6-(trifluoromethyl)-3H-pyrido[1,2-c]pyrimidin-3-one;   4-amino-1-(2-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one;   4-amino-7-cyclopropyl-1-[(1R)-1-[(3S)-oxolan-3-yl]ethyl]pyrido[2,3-d]pyrimidin-2-one;   4-amino-7-cyclopropyl-1-[(1R)-1-[(3R)-oxolan-3-yl]ethyl]pyrido[2,3-d]pyrimidin-2-one;   3-(4-amino-6-chloro-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1 (2H)-yl)-2-methoxybenzonitrile;   4-amino-7-cyclopropyl-1-(4-oxaspiro[2.5]octan-8-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-6-chloro-7-cyclopropyl-1-(2-methoxypyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one;   4-amino-7-cyclopropyl-1-(4-fluoro-2-methylphenyl)pyrido[2,3-d]pyrimidin-2-one;   4-amino-7-cyclopropyl-1-(3-ethylphenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one,   4-amino-7-cyclopropyl-1-(m-tolyl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-cyclopropyl-1-(3,5-difluorophenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-cyclopropyl-1-(6-methoxypyridin-2-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-cyclopropyl-1-(3-methoxyphenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-cyclopropyl-1-(2,3-difluorophenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-cyclopropyl-1-phenylpyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-cyclopropyl-1-(1-(oxazol-5-yl)ethyl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   3-(4-amino-2-oxo-7-(trifluoromethyl)quinazolin-1 (2H)-yl)-2-methylbenzonitrile;   3-(4-amino-2-oxo-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-1 (2H)-yl)-2-methylbenzonitrile;   4-amino-7-cyclopropyl-1-(2,6-difluorophenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-cyclopropyl-1-(2-fluorophenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-cyclopropyl-1-(3-fluorophenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-cyclopropyl-1-[1-(oxetan-3-yl)ethyl]pyrido[2,3-d]pyrimidin-2-one;   4-amino-7-(difluoromethoxy)-1-(2-methylphenyl)pyrido[2,3-d]pyrimidin-2-one;   4-amino-7-cyclopropyl-1-(1-pyridin-2-ylethyl)pyrido[2,3-d]pyrimidin-2-one;   4-amino-1-(2-methyl-3-pyridyl)-7-(2,2,2-trifluoroethyl)quinazolin-2-one hydrochloride;   4-amino-7-cyclopropyl-1-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-1-(2-chloropyridin-3-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-2-cyclopentyl-7-(2-methyl-3-pyridyl)pyrazolo[3,4-d]pyrimidin-6-one;   4-amino-5-chloro-1-(2-methylpyridin-3-yl)-7-(trifluoromethyl)quinazolin-2 (1H)-one;   4-amino-1-(3-fluoro-2-methylphenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-cyclopropyl-1-(1H-indol-4-yl)pyrido[2,3-d]pyrimidin-2-one;   4-amino-7-cyclopropyl-1-[6-(trifluoromethoxy)pyridin-2-yl]pyrido[2,3-d]pyrimidin-2-one;   4-amino-1-(2,3-dihydrobenzofuran-4-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one;   4-amino-1-(3-chloro-2-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one;   4-amino-1-(2,3-dihydro-1-benzofuran-4-yl)-7-(trifluoromethoxy)quinazolin-2-one;   4-amino-1-(3-fluoro-2-methylphenyl)-7-(trifluoromethoxy)quinazolin-2-one;   3-[4-amino-2-oxo-7-(trifluoromethoxy)quinazolin-1-yl]-2-methylbenzonitrile;   4-amino-7-cyclopropyl-1-(2,3-dihydro-1H-indol-4-yl)pyrido[2,3-d]pyrimidin-2-one;   4-amino-1-(2-chloro-5-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one;   4-amino-1-(2-chloro-4-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-cyclopropyl-1-(2,5-difluorophenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-(ethylamino)-1-(o-tolyl)quinazolin-2-one;   4-amino-1-(3-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one;   3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1 (2H)-yl)benzonitrile;   4-amino-7-(difluoromethoxy)-1-(4-oxaspiro[2.5]octan-8-yl)quinazolin-2 (1H)-one;   1-amino-4-(2-chlorophenyl)-6-(trifluoromethyl)pyrido[1,2-c]pyrimidin-3-one;   4-amino-1-(benzo[d]oxazol-4-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-cyclopropyl-1-(3,4-difluorophenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1 (2H)-yl)-2-methylbenzonitrile;   3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1 (2H)-yl)-2-methylbenzonitrile;   4-amino-7-(difluoromethoxy)-1-(o-tolyl)quinazolin-2 (1H)-one;   3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-2-chlorobenzonitrile;   4-amino-7-cyclopropyl-1-[(8S)-4-oxaspiro[2.5]octan-8-yl]pyrido[2,3-d]pyrimidin-2-one;   4-amino-7-cyclopropyl-1-[(8R)-4-oxaspiro[2.5]octan-8-yl]pyrido[2,3-d]pyrimidin-2-one;   4-amino-1-(1H-benzo[d]imidazol-4-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-cyclopropyl-1-(1H-indazol-4-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-cyclopropyl-1-(2,3-dimethylphenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-1-(2-chloropyridin-3-yl)-7-(difluoromethoxy)quinazolin-2 (1H)-one;   4-amino-1-(2-chloropyridin-3-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-1-(2-chloropyridin-3-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-(difluoromethoxy)-1-(m-tolyl)quinazolin-2 (1H)-one;   4-amino-7-(difluoromethoxy)-1-(2-fluoro-3-methylphenyl)quinazolin-2 (1H)-one;   4-amino-7-cyclopropyl-1-(2-(trifluoromethyl)phenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-cyclopropyl-1-(3-(fluoromethyl)-2-methylphenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-1-(2-chloro-3-methylphenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one;   4-amino-1-(3-chloro-2-methylphenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one;   4-amino-7-cyclopropyl-1-(2,3-dichlorophenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-cyclopropyl-1-(2-fluoro-3-methylphenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1 (2H)-yl)-2-fluorobenzonitrile;   (S)-4-amino-7-cyclopropyl-1-(oxepan-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   (R)-4-amino-7-cyclopropyl-1-(oxepan-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-cyclopropyl-1-(3-hydroxy-2-methylphenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-(difluoromethoxy)-1-(3-fluoro-2-methylphenyl)quinazolin-2 (1H)-one;   4-amino-7-cyclopropyl-1-[rac-(2S,3S)-2-methyltetrahydropyran-3-yl]pyrido[2,3-d]pyrimidin-2-one;   4-amino-1-(benzo[d]thiazol-7-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-cyclopropyl-1-((2S,3R)-2-methyltetrahydro-2H-pyran-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-cyclopropyl-1-((2R,3S)-2-methyltetrahydro-2H-pyran-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   (−)-4-amino-1-(2-chloro-3-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one;   (+)-4-amino-1-(2-chloro-3-fluorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one;   (−)-4-amino-1-(2-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one;   (+)-4-amino-1-(2-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-cyclopropyl-6-(difluoromethoxy)-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2-one;   4-amino-7-cyclopropyl-1-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)pyrido[2,3-d]pyrimidin-2-one; formic acid;   4-(2-chlorophenyl)-6-cyclopropyl-1-imino-pyrido[1,2-c]pyrimidin-3-one; formic acid;   4-amino-7-cyclopropyl-1-[2-(trifluoromethoxy)phenyl]pyrido[2,3-d]pyrimidin-2-one;   4-amino-1-(2-chloro-3-pyridyl)-7-(trifluoromethoxy)quinazolin-2-one;   4-amino-7-cyclopropyl-1-(6-(difluoromethoxy)pyridin-2-yl)pyrido[2,3-d]pyrimidin-2(1H)-one;   4-amino-7-cyclopropyl-1-(1,4-dioxepan-6-yl)pyrido[2,3-d]pyrimidin-2-one; and   4-amino-7-cyclopropyl-1-(3-fluoro-2-methylphenyl)quinazolin-2-one;   or pharmaceutically acceptable salts thereof.   
     
     
         49 . The compound of  claim 1 , selected from the group consisting of:
 4-amino-7-cyclopropyl-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-cyclopropyl-1-(2-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   3-(4-amino-7-cyclopropyl-2-oxopyrido[2,3-d]pyrimidin-1 (2H)-yl)-2-methylbenzonitrile;   4-amino-7-cyclopropyl-1-(2,3-dihydrobenzofuran-4-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-cyclopropyl-1-(3-fluoro-2-methylphenyl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-cyclopropyl-1-(oxan-3-yl)pyrido[2,3-d]pyrimidin-2-one;   4-amino-7-(difluoromethoxy)-1-(2-methylpyridin-3-yl)quinazolin-2 (1H)-one;   4-amino-1-(2-methylpyridin-3-yl)-7-(trifluoromethoxy)quinazolin-2 (1H)-one;   4-amino-7-cyclopropyl-1-(2,3-dihydrobenzofuran-4-yl)quinazolin-2 (1H)-one;   4-amino-7-cyclopropyl-1-(2,3-dihydrobenzofuran-7-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-1-(2-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2-one;   4-amino-7-cyclopropyl-1-(4-oxaspiro[2.5]octan-8-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-1-(2-chloropyridin-3-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-(difluoromethoxy)-1-(2-methylphenyl)pyrido[2,3-d]pyrimidin-2-one;   3-(4-amino-2-oxo-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-1 (2H)-yl)-2-methylbenzonitrile;   4-amino-7-cyclopropyl-1-(m-tolyl)pyrido[2,3-d]pyrimidin-2 (1H)-one;   4-amino-7-cyclopropyl-1-[(8S)-4-oxaspiro[2.5]octan-8-yl]pyrido[2,3-d]pyrimidin-2-one;   4-amino-7-cyclopropyl-1-[(8R)-4-oxaspiro[2.5]octan-8-yl]pyrido[2,3-d]pyrimidin-2-one;   (R)-4-amino-7-cyclopropyl-1-(oxepan-3-yl)pyrido[2,3-d]pyrimidin-2 (1H)-one; and   4-amino-7-cyclopropyl-1-((2S,3R)-2-methyltetrahydro-2H-pyran-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one;   or pharmaceutically acceptable salts thereof.   
     
     
         50 . A compound of  claim 1  for use as a therapeutically active substance. 
     
     
         51 . Pharmaceutical compositions comprising compounds of formula I or II of  claim 1  or their pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients. 
     
     
         52 . Compounds of formula I or II of  claim 1  or their pharmaceutically acceptable salts above for use as therapeutically active substances. 
     
     
         53 . Compounds of formula I or II of  claim 1  or their pharmaceutically acceptable salts for the use in the treatment, prevention and/or delay of progression of Lung Adenocarcinoma, Melanoma, Pancreatic Adenocarcinoma, Head and Neck Squamous Cell Carcinoma, Lung Squamous Cell Carcinoma, Esophageal Carcinoma, Glioblastmoa Multiforme, and Mesothelioma. 
     
     
         54 . (canceled) 
     
     
         55 . A method for the treatment or prevention of Lung Adenocarcinoma, Melanoma, Pancreatic Adenocarcinoma, Head and Neck Squamous Cell Carcinoma, Lung Squamous Cell Carcinoma, Esophageal Carcinoma, Glioblastmoa Multiforme, and Mesothelioma, which method comprises administering compounds of formula I of  claim 1  or their pharmaceutically acceptable salts as defined above to a subject. 
     
     
         56 . (canceled) 
     
     
         57 . The use of compounds of formula of  claim 1  or their pharmaceutically acceptable salts for the treatment, prevention and/or delay of progression of Lung Adenocarcinoma, Melanoma, Pancreatic Adenocarcinoma, Head and Neck Squamous Cell Carcinoma, Lung Squamous Cell Carcinoma, Esophageal Carcinoma, Glioblastmoa Multiforme, and Mesothelioma. 
     
     
         58 . (canceled) 
     
     
         59 . The use of compounds of formula I of  claim 1  or their pharmaceutically acceptable salts for the preparation of medicaments for the treatment or prevention of Lung Adenocarcinoma, Melanoma, Pancreatic Adenocarcinoma, Head and Neck Squamous Cell Carcinoma, Lung Squamous Cell Carcinoma, Esophageal Carcinoma, Glioblastmoa Multiforme, and Mesothelioma. 
     
     
         60 . (canceled) 
     
     
         61 . (canceled)